Gastroparesis, which means weak stomach, is a paralysis of the gastrointestinal (GI) system. It is a type of neuropathy causing stoppage or incorrect functioning of the autonomic nervous system resulting in delayed gastric emptying following ingestion of a meal. The stomach has two parts. The upper portion called the proximal stomach or fundus is where swallowed food and liquid collect. The lower portion called the distal stomach or antrum is where food is churned back and forth until it is broken into small fragments and then expelled into the duodenum which is the first part of the small intestine. Solid phase emptying is determined by powerful circular contractions of the antrum.
The vagus nerve controls the movement of food through the digestive tract. In normal individuals, a coordinated wave of activity sweeps across the antrum about three times a minute following ingestion of a solid meal causing the stomach to contract. Namely, the stomach empties within about 90-120 minutes after eating. When the vagus nerve is damaged or dysfunctional, stomach muscles do not work properly and stomach contraction becomes sluggish and/or less frequent. As a result, the movement of food is slowed or stopped. Gastroparesis is the medical term for this condition.
In individuals with gastroparesis, the electrical wave slows and the stomach contracts less frequently and sometimes with less force causing food to sit in the stomach. Normally, stomach muscles contract about three times a minute and the stomach empties within about 90-120 minutes after eating.
Major causes of gastroparesis include, but are not limited to, postviral syndromes, anorexia nervosa, surgery on the stomach or vagus nerve, medications, particularly anticholinergics and narcotics (or any other drugs that slow contractions in the intestine), gastroesophageal reflux diseases, smooth muscle disorders such as amyloidosis and scleroderma, nervous system diseases such as abdominal migraine and Parkinson's disease, and metabolic disorders such as hypothyroidism, multiple sclerosis, and drugs including anticholinergics, calcium channel blockers, opioids, antidepressants.
In 40% of the cases, gastroparesis has no known cause. The disease, however, occurs in approximately 25% to 35% of diabetics with one study finding the prevalence of the disorder to be as high as 59%. [{NPL 1} Soykan, I. et al., Demography, clinical characteristics, psychological and abuse profiles treatment and long-term follow-up of patients with gastroparesis, Dig. Dis. Sci. 11: 2398-2404, 1998; {NPL 2} Hiba, R., Is there a difference in the prevalence of gastrointestinal symptoms between type 1 and type 2 diabetics? Gastroenterology, 4: A79, 1999]. Therefore diabetes is also a major cause of gastroparesis. Blood glucose levels of diabetic patients often remain high for long periods. High blood glucose causes chemical changes in nerves and damages the blood vessels that carry oxygen and nutrients to the vagus nerve. As a result, at least 20% of people with Type I diabetes develop gastroparesis. Gastroparesis also occurs in people with Type II diabetes, although less often. It is not clear why the prevalence of this disease is so high in the diabetic population; however, it appears that glucose control is important since hyperglycemia causes delay in gastric emptying and exacerbates the symptoms associated with the disease.
Typical symptoms of gastroparesis include early satiety, weight loss, abdominal bloating, abdominal discomfort, epigastric pain, anorexia, nausea, and vomiting. These symptoms may be mild or severe. In addition, because food lingers in the stomach, gastroparesis can lead to complications such as bacterial overgrowth from fermentation of food, hardening of food into solid masses called bezoars that may cause nausea, vomiting, and obstruction in the stomach. Bezoars can be dangerous if they block the passage of food into the small intestine.
Treatments currently available are not fully efficacious and are often associated with undesirable adverse events. For example, prokinetic and antiemetic agents may be administered to treat delayed gastric emptying ({NPL 3} McCallum, R. et al. Diabetic and nondiabetic gastroparesis: Current Treatment Options Gastroenterology, 1: 1-7, 1998). The weak correlation between gastric emptying and the severity of symptoms is known ({NPL 4} Digestion, 60: 422-427, 1999; {NPL 5} Diabetes Care, 24: 1264-1269, 2001). Promotion of gastric emptying does not simply lead to the treatment of gastroparesis, which makes the treatment of gastroparesis difficult. The effective drug with enough safety is limited ({NPL 6} Gastroenterol Hepatol, 6: 1-16, 2010).
Intravenous erythromycin is often the treatment of choice for patients who cannot take oral medications due to the severity of the disease or other problems. However, erythromycin can cause GI toxicity, ototoxicity, pseudomembranous colitis, and the induction of resistant bacterial strains. Erythromycin is recognized that the effect is reduced by long-term use. No symptom improvement effect in patients with gastroparesis is observed in motilide, motilin-like macrolide. At a dose of promoting gastric emptying, motilin agonists (e.g. Erythromycin) cause accommodation inhibition, and worse early satiety of patients with gastroparesis.
For patients that can take oral medications, cisapride, which is 5-HT4 agonist, is probably the most efficacious. Cisapride has been withdrawn for safety reasons. Adverse events of cisapride include abdominal discomfort and increased frequency of bowel movements. In addition, there are important drug interactions that may cause heart arrhythmias; therefore, the drug is severely restricted as to its availability in the world. 5-HT4 agonists seem to be no problem from the mechanistic aspect in symptom improvement, because cisapride was applied to gastroparesis. But no 5-HT4 agonists have been clinically available yet.
Metoclopramide in oral and injectable forms is the only currently approved treatment for gastroparesis in the United States. Metoclopramide is a dopamine antagonist and acts by stimulating stomach muscle contractions to help empty food. Traditionally, treatment of gastroparesis with Metoclopramide is via injection or oral route.
Metoclopramide is currently available in tablet form, injection form, and syrup form, under the name REGLAN (A.H. Robbins Company). Tachyphylaxis may develop to the beneficial effects of Metoclopramide in some patients.
However Metoclopramide has a significant profile of adverse events that include fatigue, sleepiness, depression, anxiety, and difficulty with physical movement. Mental depression has occurred in patients with and without prior history of depression.
Symptoms range from mild to severe, including suicidal ideation and suicide. Other adverse events include involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, and dystonic reactions such as strider and dyspnea.
Further, domperidone is a less potent version of metoclopramide. In addition, anti-emetics are sometimes used to relieve one or more symptoms of gastroparesis (i.e., nausea, vomiting), but, unlike, for example, metoclopramide do not treat the underlying disorder by increasing gastric motility. In fact, gastroparesis involves multiple symptoms in addition to emesis, and the skilled practitioner would not expect a drug that treats emesis alone to be an adequate treatment of gastroparesis. Domperidone is not available in the United States for QT prolongation.
In patients with gastroparesis, absorption through the GI tract is unpredictable and far less effective the normal, with predictability and effectiveness having an inverse relationship to the severity of the symptoms.
Thus, the more severe the symptoms, the less likely that oral administration becomes an option for the treatment. Further complicating matter of oral administration is the fact that patients with gastroparesis often have symptoms such as vomiting and nausea. If vomiting takes place, the amount of oral dosage that remains in the stomach is unknown, and the result of treatment is even less predictable.